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2024 Apr 15
Vitamin D in Melanoma: Potential Role of Cytochrome P450 Enzymes

DOI: 10.3390/life14040510

Abstract
Vitamin D is a promising anticancer agent for the prevention and treatment of several cancers, including melanoma. Low 25-hydroxyvitamin D levels, a routinely used marker for vitamin D, have been suggested as one of the factors in the development and progression of melanoma. The parent vitamin D needs activation by cytochrome P450 (CYP) enzymes to exert its actions via the vitamin D receptor (VDR). This review discusses the role of vitamin D in melanoma and how CYP-mediated metabolism can potentially affect the actions of vitamin D. Through interacting with the retinoid X receptor, VDR signaling leads to anti-inflammatory, antioxidative, and anticancer actions. Calcitriol, the dihydroxylated form of vitamin D3, is the most active and potent ligand of VDR. CYP27A1, CYP27B1, and CYP2R1 are involved in the activation of vitamin D, whereas CYP24A1 and CYP3A4 are responsible for the degradation of the active vitamin D. CYP24A1, the primary catabolic enzyme of calcitriol, is overexpressed in melanoma tissues and cells. Several drug classes and natural health products can modulate vitamin D-related CYP enzymes and eventually cause lower levels of vitamin D and its active metabolites in tissues. Although the role of vitamin D in the development of melanoma is yet to be fully elucidated, it has been proposed that melanoma prevention may be significantly aided by increased vitamin D signaling. Furthermore, selective targeting of the catabolic enzymes responsible for vitamin D degradation could be a plausible strategy in melanoma therapy. Vitamin D signaling can be improved by utilizing dietary supplements or by modulating CYP metabolism. A positive association exists between the intake of vitamin D supplements and improved prognosis for melanoma patients. Further investigation is required to determine the function of vitamin D supplementation and specific enzyme targeting in the prevention of melanoma.

Dr. Nathan Goodyear, an integrative cancer physician and director of Brio Medical, an integrative cancer treatment center in Scottsdale, Arizona, stresses vitamin D’s essential role in immune functionality and its influence on chronic diseases, like cancer. He explains, “The immune system does not work well if vitamin D is not optimal,” emphasizing its role in cancer, where immune strength is crucial.

Recent research, including melanoma studies, indicates that vitamin D supplementation can enhance treatment responses and prolong survival in cancer patients, even with currently insufficient daily dosage recommendations.

2023 Jul 1
Vitamin D supplementation increases objective response rate and prolongs progression-free time in patients with advanced melanoma undergoing anti-PD-1 therapy

DOI: 10.1002/cncr.34718

Abstract
Background: Vitamin D3 is a prohormone with pleiotropic effects, including modulating the functions of the immune system and may affect the effectiveness of anti-PD-1 treatment in patients with cancer. According to the literature, the potential mechanism of vitamin D's influence on the effectiveness of therapy is most likely related to the amount and activity of tumor-infiltrating lymphocytes. There are data showing the effect of vitamin D on cells regulating the activity of CD8 lymphocytes.

Methods: A total of 200 patients with advanced melanoma were included in the study. All patients received anti-PD-1 immunotherapy (nivolumab or pembrolizumab) as first-line treatment. Serum vitamin D levels were measured in patients both before and every 12 weeks during treatment. Part of the group had vitamin D measured retrospectively from the preserved serum. The other part of the supplementation group was tested prospectively.

Results: The response rate in the group with low vitamin D levels and not supplemented was 36.2%, whereas in the group with normal baseline levels or a normal level obtained with supplementation was 56.0% (p = .01). Moreover, progression-free survival in these groups was 5.75 and 11.25 months, respectively (p = .03). In terms of overall survival, there was also a difference in favor of the group with normal vitamin D levels (27 vs. 31.5 months, respectively; p = .39).

Conclusions: In our opinion, maintaining the vitamin D level within the normal range during anti-PD-1 immunotherapy in advanced melanoma patients should be a standard procedure allowing the improvement of treatment outcomes.